tbuckley/cabot-search huggingface dataset:
307 The study design of a trial of dupilumab in adult patients with bullous pemphigoid (BP): LIBERTY-BP ADEPT
Authors: Dedee F Murrell, Pascal Joly, Victoria P Werth, Elizabeth Laws, Leda P Mannent, Bethany Beazley, Ariane Dubost-Brama, Arsalan Shabbir
Journal: British Journal of Dermatology (2023)

Abstract BP is a rare autoimmune skin-blistering disorder with a profound negative impact on quality of life, associated with burdensome morbidity and possible mortality. There is a need for effective targeted therapies with a demonstrated safety profile for BP. Dupilumab is a fully human monoclonal antibody that blocks the shared receptor component for interleukin (IL)-4 and IL-13, key and central drivers of type 2 inflammation that may play a role in BP. Published case series describes the use of dupilumab in patients with BP, but it has not been formally assessed in a clinical trial for BP. We describe the design of the LIBERTY-BP ADEPT trial (NCT04206553) that aims to investigate the efficacy and safety of dupilumab in achieving sustained remission off oral corticosteroids (OCS) in patients with moderate-to-severe BP. LIBERTY-BP ADEPT is a global, randomized, double-blind, placebo-controlled, parallel-group study consisting of a 35-day screening period, a 52-week double-blind treatment period and a 12-week follow-up period. Inclusion criteria include age 18–90 years and clinical features of BP with a confirmed diagnosis based on histopathology, immunopathology, and serology. Exclusion criteria include previous treatment with IL-4 or IL-13 antagonists or systemic or medium-to-high potency topical corticosteroids within 7 days of the baseline visit. All patients receive standard OCS to control disease activity at the start of the treatment period. Post randomization, after 2 weeks of sustained remission, OCS is to be gradually tapered and discontinued as long as disease control is maintained. The primary endpoint is the proportion of patients achieving sustained remission at week 36. Key secondary endpoints include total cumulative OCS dose, percent change in weekly average daily Peak Pruritus Numerical Rating Scale (NRS) score, and proportion of patients with improved daily Peak Pruritus NRS score ≥4 from baseline to week 36. LIBERTY-BP ADEPT aims to enroll 98 patients; enrollment is ongoing and will include more than 17 sites in Europe. BP shares pathophysiological pathways with type 2 inflammatory diseases mediated by IL-4 and IL-13. The ongoing LIBERTY-BP ADEPT study is the first randomized, controlled trial designed to evaluate the efficacy and safety of dupilumab in patients with moderate-to-severe BP.
315 A patient survey to identify atopic dermatitis prescription treatment access barriers
Authors: Allison R Loiselle, Isabelle J C Thibau, Michele Guadalupe, Lisa Butler, Wendy Smith Begolka
Journal: British Journal of Dermatology (2023)

Abstract Atopic dermatitis (AD) is the most prevalent form of eczema and is a chronic disease with a relapsing-remitting nature. Multiple treatment options exist, yet little is known about patients’ ability to obtain recommended prescription treatments. The aim of this web-based survey was to ascertain the frequency, causes and patient impact of insurance delays and denials for AD prescription treatments. Adult AD patients (18 + years) or caregivers of pediatric AD patients were recruited to complete a survey about experiences with prescription treatment access in the last 12 months. Responses from 1234 AD patients (42.0 ± 16.7 years) and 248 caregivers (8.5 ± 4.7 years) were included in the analysis; 55.4% (n = 680) reported moderate or severe AD. Overall, there were 789 insurance delays or denials for AD prescriptions, with 37.0% (457/1234) of respondents experiencing at least one in the past 12 months. Overall, the majority of delays/denials were for topical steroids (38.3%; 302/789), which is likely due to the high number of patients using one or more topical steroid prescriptions (82.5%; 1018/1234). However, the highest individual drug class burden was on biologics, for which 38.7% of all prescriptions (122/315) faced a delay or denial. Coverage denials were caused primarily by step therapy (25.5%), and delays by prior authorization (61.1%), and only 62.0% of respondents said they would know what to do if they faced an issue getting a prescription covered by their insurer. Patient-reported impacts of prescription denials and delays included: AD flares (85.0%; n = 255), needing alternate medications (72.3%; n = 217), emergency care (49.0%; n = 147) and giving up on treatment altogether (59.0%; n = 177). Patients with AD and their families frequently experience issues obtaining recommended therapies which can result in detrimental health and quality of life impacts. As many as one-third of patients may not know how to respond if their prescriptions are met with insurance delays or denials, further exacerbating those impacts. These data may help identify strategies to improve timely and beneficial therapeutic access.
318 Facilitating mentorship for caregivers of children with atopic dermatitis: the supporting eczema caregivers initiative
Authors: Michelle Tu, Lauren Amaro, Bennett Kidder, Keri Kelley, Korey Capozza, Alan Schwartz
Journal: British Journal of Dermatology (2023)

Abstract Caregivers of children with atopic dermatitis (AD) report high levels of stress, feelings of failure and isolation, and a need for social support. These socioemotional effects accumulate over time, often resulting in dramatic changes in career, finances and social activities for caregivers and families when childhood AD is poorly controlled. Psychosocial support and supportive relationships are critical to handling stressful life events. The present study assesses a psychosocial support programme for parents of children with AD. This mentorship program’s primary objective was to promote improvements in stress, resilient coping and loneliness among AD caregivers. Participants were randomized to an email-only group (n = 40) or a one-to-one mentorship pairing (n = 17). We collected measures of stress, coping resilience, loneliness, AD severity and program satisfaction at baseline, 6 weeks and 12 weeks. Eczema severity significantly decreased overall from baseline to 6 weeks (P &amp;lt; 0.001) and remained decreased at 12 weeks (P &amp;lt; 0.001 vs. baseline). There was no significant difference between groups or change in stress, resilience or loneliness over time. Qualitative data demonstrated high program satisfaction. While there was no change in loneliness, resilience or stress, we found a reduction in self-reported eczema symptoms. Continued reduction in these symptoms could affect the overall quality of life, which in turn could yield improved measures of loneliness, resilience and stress.
Associations of tissue tumor mutational burden and mutational status with clinical outcomes in KEYNOTE-042: pembrolizumab versus chemotherapy for advanced PD-L1-positive NSCLC
Authors: T.S.K. Mok, G. Lopes, B.C. Cho, D.M. Kowalski, K. Kasahara, Y.-L. Wu, G. de Castro, H.Z. Turna, R. Cristescu, D. Aurora-Garg, A. Loboda, J. Lunceford, J. Kobie, M. Ayers, M.C. Pietanza, B. Piperdi, R.S. Herbst
Journal: Annals of Oncology (2023)
β-actin mediated H3K27ac changes demonstrate the link between compartment switching and enhancer-dependent transcriptional regulation
Authors: Syed Raza Mahmood, Nadine Hosny El Said, Kristin C. Gunsalus, Piergiorgio Percipalle
Journal: Genome biology (2023)

Abstract Background Recent work has demonstrated that three-dimensional genome organization is directly affected by changes in the levels of nuclear cytoskeletal proteins such as β-actin. The mechanisms which translate changes in 3D genome structure into changes in transcription, however, are not fully understood. Here, we use a comprehensive genomic analysis of cells lacking nuclear β-actin to investigate the mechanistic links between compartment organization, enhancer activity, and gene expression. Results Using HiC-Seq, ATAC-Seq, and RNA-Seq, we first demonstrate that transcriptional and chromatin accessibility changes observed upon β-actin loss are highly enriched in compartment-switching regions. Accessibility changes within compartment switching genes, however, are mainly observed in non-promoter regions which potentially represent distal regulatory elements. Our results also show that β-actin loss induces widespread accumulation of the enhancer-specific epigenetic mark H3K27ac. Using the ABC model of enhancer annotation, we then establish that these epigenetic changes have a direct impact on enhancer activity and underlie transcriptional changes observed upon compartment switching. A complementary analysis of fibroblasts undergoing reprogramming into pluripotent stem cells further confirms that this relationship between compartment switching and enhancer-dependent transcriptional change is not specific to β-actin knockout cells but represents a general mechanism linking compartment-level genome organization to gene expression. Conclusions We demonstrate that enhancer-dependent transcriptional regulation plays a crucial role in driving gene expression changes observed upon compartment-switching. Our results also reveal a novel function of nuclear β-actin in regulating enhancer function by influencing H3K27 acetylation levels.
The management of light chain (AL) amyloidosis in Europe: clinical characteristics, treatment patterns, and efficacy outcomes between 2004 and 2018
Authors: Giovanni Palladini, Stefan Schönland, Giampaolo Merlini, Paolo Milani, Arnaud Jaccard, Frank Bridoux, Meletios A. Dimopoulos, Sriram Ravichandran, Ute Hegenbart, Wilfried Roeloffzen, M. Teresa Cibeira, Hermine Agis, Monique C. Minnema, Rui Bergantim, Roman Hájek, Cristina João, Alexandros Leonidakis, Giorgos Cheliotis, Pieter Sonneveld, Efstathios Kastritis, Ashutosh Wechalekar
Journal: Blood Cancer Journal (2023)

Systemic light-chain (AL) amyloidosis is a rare and debilitating disease. Advances have been made in new treatments in recent years, yet real-world data on the management of the disease are scarce. EMN23 is a retrospective, observational study of patients who initiated first-line treatment in 2004-2018 in Europe, presenting the demographics, clinical characteristics, treatment patterns, and outcomes, from 4480 patients. Regimens based on bortezomib were the most frequently used as first-line therapy; only 6.2% of the patients received autologous stem cell transplant. Hematologic responses improved post-2010 (67.1% vs 55.6% pre-2010). The median overall survival (OS) was 48.8 (45.2-51.7) months; 51.4 (47.3-57.7) months pre-2010 and 46.7 (41.3-52.2) months post-2010. Early mortality was 13.4% and did not improve (11.4% vs 14.4% pre- and post-2010); furthermore, it remained high in patients with advanced cardiac disease (over 39% for stage IIIb). There was a significant improvement for stage IIIa (14.2 vs 30.7 months, p = 0.0170) but no improvement for stage IIIb patients (5.0 vs 4.5 months). This European real-world study of AL-amyloidosis emphasizes the unmet needs of early diagnosis, and the lack of improvement in survival outcomes of the frail stage IIIb population, despite the introduction of new therapies in recent years.
Outcomes for International Metastatic Renal Cell Carcinoma Database Consortium Prognostic Groups in Contemporary First-line Combination Therapies for Metastatic Renal Cell Carcinoma
Authors: Matthew S. Ernst, Vishal Navani, J. Connor Wells, Frede Donskov, Naveen Basappa, Chris Labaki, Sumanta K. Pal, Luis Meza, Lori A. Wood, D. Scott Ernst, Bernadett Szabados, Rana R. McKay, Francis Parnis, Cristina Suarez, Takeshi Yuasa, Aly-Khan Lalani, Ajjai Alva, Georg A. Bjarnason, Toni K. Choueiri, Daniel Y.C. Heng
Journal: European Urology (2023)

The combination of immuno-oncology (IO) agents ipilimumab and nivolumab (IPI-NIVO) and vascular endothelial growth factor targeted therapies (VEGF-TT) combined with IO (IO-VEGF) are current standard of care first-line treatments for metastatic renal cell carcinoma (mRCC).
Cryo‐EM structure of orphan G protein‐coupled receptor GPR21
Authors: Thian‐Sze Wong, Wei Gao, Geng Chen, Chen Qiu, Guodong He, Fang Ye, Zhangsong Wu, Zicheng Zeng, Yang Du
Journal: MedComm (2023)

Abstract GPR21 belongs to class A orphan G protein‐coupled receptor (GPCR). The endogenous ligands for human GPR21 remain unidentified. GPR21 expression is associated with developing type 2 diabetes (T2DM), a multifactorial metabolic disease caused by pancreatic β‐cell dysfunction, decreasing insulin production, insulin resistance, and obesity. Animal studies suggested that GPR21 is a potential therapeutic target for T2DM treatment. The underlying mechanisms leading to GPR21 self‐activation remain unknown. In our co‐expression analysis, we noted that GPR21 could also form a stable complex with an unreported Gα protein subtype, Gαs. To gain further insights into the structural mechanisms of GPR21 activation, we employed cryo‐electron microscopy (cryo‐EM) and single‐particle analysis to resolve the high‐resolution structure of GPR21‐Gαs complexes. The clear electron density map of the GPR21‐Gαs provided direct evidence that GPR21 could couple to Gαs protein at physiological conditions. Thus, GPR21 might mediate previously unexplored pathways in normal or pathological conditions, which warrants further investigation. Structure‐guided mutagenesis and biochemical analysis revealed that extracellular loop 2 (ECL2) of GPR21 is essential for the receptor transducing intracellular signal via cAMP. Together, the new structure data reveal a novel signaling cascade of human GPR21 mediated by ECL2 and provide fundamental information for future structure‐based drug development.
Rhinovirus infection of the airway epithelium enhances mast cell immune responses via epithelial-derived interferons
Authors: Ryan C. Murphy, Ying Lai, Matthew C. Altman, Kaitlyn A. Barrow, Kimberly A. Dill-McFarland, Matthew Liu, Jessica A. Hamerman, Adam Lacy-Hulbert, Adrian M. Piliponsky, Steven F. Ziegler, William A. Altemeier, Jason S. Debley, Sina A. Gharib, Teal S. Hallstrand
Journal: Journal of Allergy and Clinical Immunology (2023)
FLCN-Driven Functional Adrenal Cortical Carcinoma with High Mitotic Tumor Grade: Extending the Endocrine Manifestations of Birt-Hogg-Dubé Syndrome
Authors: Renee Hofstedter, María Carolina Sanabria-Salas, Maria Di Jiang, Shereen Ezzat, Ozgur Mete, Raymond H. Kim
Journal: Endocrine Pathology (2023)
A pangenome analysis pipeline provides insights into functional gene identification in rice
Authors: Jian Wang, Wu Yang, Shaohong Zhang, Haifei Hu, Yuxuan Yuan, Jingfang Dong, Luo Chen, Yamei Ma, Tifeng Yang, Lian Zhou, Jiansong Chen, Bin Liu, Chengdao Li, David Edwards, Junliang Zhao
Journal: Genome biology (2023)

Abstract Background A pangenome aims to capture the complete genetic diversity within a species and reduce bias in genetic analysis inherent in using a single reference genome. However, the current linear format of most plant pangenomes limits the presentation of position information for novel sequences. Graph pangenomes have been developed to overcome this limitation. However, bioinformatics analysis tools for graph format genomes are lacking. Results To overcome this problem, we develop a novel strategy for pangenome construction and a downstream pangenome analysis pipeline (PSVCP) that captures genetic variants’ position information while maintaining a linearized layout. Using PSVCP, we construct a high-quality rice pangenome using 12 representative rice genomes and analyze an international rice panel with 413 diverse accessions using the pangenome as the reference. We show that PSVCP successfully identifies causal structural variations for rice grain weight and plant height. Our results provide insights into rice population structure and genomic diversity. We characterize a new locus ( qPH8-1 ) associated with plant height on chromosome 8 undetected by the SNP-based genome-wide association study (GWAS). Conclusions Our results demonstrate that the pangenome constructed by our pipeline combined with a presence and absence variation-based GWAS can provide additional power for genomic and genetic analysis. The pangenome constructed in this study and the associated genome sequence and genetic variants data provide valuable genomic resources for rice genomics research and improvement in future.
Tom Nolan’s research reviews—26 January 2023
Authors: Tom Nolan
Journal: BMJ (2023)

Battle of the loopsThe recent Christmas issue of The BMJ highlighted examples of mis-spelt antimicrobials including cefouroxime (4× better), trimethoprime (comes with free delivery), and, my favourite, tazosin (prescribe in haste, repent at leisure).If we searched the most mis-spelt drugs of all, my bet would be on furosemide to top the charts.I can't be the only person who still hasn't fully come to terms with the inconvenient "u", added when the UK switched from British Approved Names to International Non-Proprietary Names 20 years ago.
Deep learning system to predict the 5-year risk of high myopia using fundus imaging in children
Authors: Li Lian Foo, Gilbert Yong San Lim, Carla Lanca, Chee Wai Wong, Quan V. Hoang, Xiu Juan Zhang, Jason C. Yam, Leopold Schmetterer, Audrey Chia, Tien Yin Wong, Daniel S. W. Ting, Seang-Mei Saw, Marcus Ang
Journal: npj Digital Medicine (2023)

Our study aims to identify children at risk of developing high myopia for timely assessment and intervention, preventing myopia progression and complications in adulthood through the development of a deep learning system (DLS). Using a school-based cohort in Singapore comprising of 998 children (aged 6-12 years old), we train and perform primary validation of the DLS using 7456 baseline fundus images of 1878 eyes; with external validation using an independent test dataset of 821 baseline fundus images of 189 eyes together with clinical data (age, gender, race, parental myopia, and baseline spherical equivalent (SE)). We derive three distinct algorithms - image, clinical and mix (image + clinical) models to predict high myopia development (SE ≤ -6.00 diopter) during teenage years (5 years later, age 11-17). Model performance is evaluated using area under the receiver operating curve (AUC). Our image models (Primary dataset AUC 0.93-0.95; Test dataset 0.91-0.93), clinical models (Primary dataset AUC 0.90-0.97; Test dataset 0.93-0.94) and mixed (image + clinical) models (Primary dataset AUC 0.97; Test dataset 0.97-0.98) achieve clinically acceptable performance. The addition of 1 year SE progression variable has minimal impact on the DLS performance (clinical model AUC 0.98 versus 0.97 in primary dataset, 0.97 versus 0.94 in test dataset; mixed model AUC 0.99 versus 0.97 in primary dataset, 0.95 versus 0.98 in test dataset). Thus, our DLS allows prediction of the development of high myopia by teenage years amongst school-going children. This has potential utility as a clinical-decision support tool to identify "at-risk" children for early intervention.
The neuroimmune axis of Alzheimer’s disease
Authors: Mehdi Jorfi, Anna Maaser-Hecker, Rudolph E. Tanzi
Journal: Genome Medicine (2023)

Abstract Alzheimer’s disease (AD) is a genetically complex and heterogeneous disorder with multifaceted neuropathological features, including β-amyloid plaques, neurofibrillary tangles, and neuroinflammation. Over the past decade, emerging evidence has implicated both beneficial and pathological roles for innate immune genes and immune cells, including peripheral immune cells such as T cells, which can infiltrate the brain and either ameliorate or exacerbate AD neuropathogenesis. These findings support a neuroimmune axis of AD, in which the interplay of adaptive and innate immune systems inside and outside the brain critically impacts the etiology and pathogenesis of AD. In this review, we discuss the complexities of AD neuropathology at the levels of genetics and cellular physiology, highlighting immune signaling pathways and genes associated with AD risk and interactions among both innate and adaptive immune cells in the AD brain. We emphasize the role of peripheral immune cells in AD and the mechanisms by which immune cells, such as T cells and monocytes, influence AD neuropathology, including microglial clearance of amyloid-β peptide, the key component of β-amyloid plaque cores, pro-inflammatory and cytotoxic activity of microglia, astrogliosis, and their interactions with the brain vasculature. Finally, we review the challenges and outlook for establishing immune-based therapies for treating and preventing AD.
Cardiac Resynchronization Therapy Improves Outcomes in Patients With Intraventricular Conduction Delay But Not Right Bundle Branch Block: A Patient-Level Meta-Analysis of Randomized Controlled Trials
Authors: Daniel J. Friedman, Sana M. Al-Khatib, Frederik Dalgaard, Marat Fudim, William T. Abraham, John G.F. Cleland, Anne B. Curtis, Michael R. Gold, Valentina Kutyifa, Cecilia Linde, Anthony S. Tang, Fatima Ali-Ahmed, Antonio Olivas-Martinez, Lurdes Y.T. Inoue, Gillian D. Sanders
Journal: Circulation (2023)

Background: Benefit from cardiac resynchronization therapy (CRT) varies by QRS characteristics; individual randomized trials are underpowered to assess benefit for relatively small subgroups. Methods: The authors analyzed patient-level data from pivotal CRT trials (MIRACLE [Multicenter InSync Randomized Clinical Evaluation], MIRACLE-ICD [Multicenter InSync ICD Randomized Clinical Evaluation], MIRACLE-ICD II [Multicenter InSync ICD Randomized Clinical Evaluation II], REVERSE [Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction], RAFT [Resynchronization-Defibrillation for Ambulatory Heart Failure], BLOCK-HF [Biventricular Versus Right Ventricular Pacing in Heart Failure Patients with Atrioventricular Block], COMPANION [Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure], and MADIT-CRT [Multicenter Automatic Defibrillator Implantation Trial – Cardiac Resynchronization Therapy]) using Bayesian Hierarchical Weibull survival regression models to assess CRT benefit by QRS morphology (left bundle branch block [LBBB], n=4549; right bundle branch block [RBBB], n=691; and intraventricular conduction delay [IVCD], n=1024) and duration (with 150-ms partition). The continuous relationship between QRS duration and CRT benefit was also examined within subgroups defined by QRS morphology. The primary end point was time to heart failure hospitalization (HFH) or death; a secondary end point was time to all-cause death. Results: Of 6264 patients included, 25% were women, the median age was 66 [interquartile range, 58 to 73] years, and 61% received CRT (with or without an implantable cardioverter defibrillator). CRT was associated with an overall lower risk of HFH or death (hazard ratio [HR], 0.73 [credible interval (CrI), 0.65 to 0.84]), and in subgroups of patients with QRS ≥150 ms and either LBBB (HR, 0.56 [CrI, 0.48 to 0.66]) or IVCD (HR, 0.59 [CrI, 0.39 to 0.89]), but not RBBB (HR 0.97 [CrI, 0.68 to 1.34]; P interaction &lt;0.001). No significant association for CRT with HFH or death was observed when QRS was &lt;150 ms (regardless of QRS morphology) or in the presence of RBBB. Similar relationships were observed for all-cause death. Conclusions: CRT is associated with reduced HFH or death in patients with QRS ≥150 ms and LBBB or IVCD, but not for those with RBBB. Aggregating RBBB and IVCD into a single “non-LBBB” category when selecting patients for CRT should be reconsidered. Registration: URL: https://www.clinicaltrials.gov ; Unique identifiers: NCT00271154, NCT00251251, NCT00267098, and NCT00180271.
Correction: circCYP24A1 facilitates esophageal squamous cell carcinoma progression through binding PKM2 to regulate NF-κB-induced CCL5 secretion
Authors: Lina Gu, Yang Sang, Xixi Nan, Yang Zheng, Fei Liu, Lingjiao Meng, Meixiang Sang, Baoen Shan
Journal: Molecular Cancer (2023)